The common theory held until recently regarding the genetic underpinning of neuropsychiatric disorders was based on the “common disease-common variant” model. According to that theory, multiple common alleles in the population contribute small-to-moderate additive or multiplicative effects to the predisposition to neuropsychiatric disorders. With the advances in genetic screening technologies this theory is now being challenged. Recent findings indicate that rare copy number variations (CNVs) may account for a substantial fraction of the overall genetic risk for neuropsychiatric disorders including schizophrenia and autism (Consortium, 2008; Stefansson et al., 2008;
Mefford et al., 2008). The 22q11.2 microdeletion was the most common CNV identified in patients with schizophrenia in a recent large scale study of patients with schizophrenia (Consortium, 2008). The 22q11.2 microdeletion is also the most common microdeletion occurring in humans and up to one third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop schizophrenia by adulthood. Thus the syndrome serves as an important model from which to learn the path leading from a well defined genetic defect to brain development and eventually to the evolution of schizophrenia.

The current very elegant study by Mukai and colleagues suggests that haploinsufficiency of a single gene from the 22q11.2 deleted region, Zdhhc8, is responsible for the microscopic neural hippocampal abnormalities present in a mouse model of the disease. Remarkably, these abnormalities were prevented with the reintroduction of enzymatically active ZDHHC8 protein. The works of Gogos and his colleagues (Paterlini et al., 2005; Stark et al., 2008) are consistently and brilliantly getting us closer to revealing the complex association between genes from the 22q11.2 region and the neuropsychiatric phenotype. If indeed haploinsuffiency of single genes like Zdhhc8, COMT, or Dgcr8 have a strong effect on abnormal brain development and the eruption of schizophrenia, it conveys an enormous potential for developing novel pathophysiologically based treatments for this refractory disease. Such treatments will target the enzymatic deficit conveyed by the genetic mutation.